The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

/pdf/cancer-related-inflammation-ltml0xgfd3.pdf

Cancer-related inflammation.

Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

/pdf/the-wnt-signaling-pathway-in-development-and-disease-z4j8s29ao8.pdf

The Wnt signaling pathway in development and disease.

MicroRNAs (miRNAs) constitute a large family of noncoding RNAs that function as guide molecules in diverse gene silencing pathways. Current efforts are focused on the regulatory function of miRNAs, while little is known about how these unusual genes themselves are regulated. Here we present the first direct evidence that miRNA genes are transcribed by RNA polymerase II (pol II). The primary miRNA transcripts (pri‐miRNAs) contain cap structures as well as poly(A) tails, which are the unique properties of class II gene transcripts. The treatment of human cells with α‐amanitin decreased the level of pri‐miRNAs at a concentration that selectively inhibits pol II activity. Furthermore, chromatin immunoprecipitation analyses show that pol II is physically associated with a miRNA promoter. We also describe, for the first time, the detailed structure of a miRNA gene by determining the promoter and the terminator of mir‐23a∼27a∼24‐2 . These data indicate that pol II is the main, if not the only, RNA polymerase for miRNA gene transcription. Our study offers a basis for understanding the structure and regulation of miRNA genes.

/pdf/microrna-genes-are-transcribed-by-rna-polymerase-ii-7trd0easzj.pdf

MicroRNA genes are transcribed by RNA polymerase II.

MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ∼22 nucleotides in length, and they are produced by two RNase III proteins--Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging.

Regulation of microRNA biogenesis

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

/pdf/identification-of-human-triple-negative-breast-cancer-3rvotimac1.pdf

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Nuclear receptor coregulators: their modification codes and regulatory mechanism by translocation.

Lysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment. In this review, we discuss the role of LSD1 in several aspects of cancer, such as hypoxia, epithelial-to-mesenchymal transition, stemness versus differentiation of cancer stem cells, as well as anti-tumor immunity. Additionally, the current understanding of the involvement of LSD1 in various other pathological processes is discussed.

/pdf/roles-of-lysine-specific-demethylase-1-lsd1-in-homeostasis-5avxexiu8g.pdf

Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases

Small ubiquitin-like modifiers (SUMOs) mediate a variety of cellular functions of protein targets mainly in the nucleus but in other cellular compartments as well, and thereby participate in maintaining cellular homeostasis. SUMO system plays important roles in transcriptional regulation, DNA damage responses, maintaining genome integrity, and signaling pathways. Thus, in some cases, loss of regulated control on SUMOylation/deSUMOylation processes causes a defect in maintaining homeostasis and hence gives a cue to cancer development and progression. Furthermore, recent studies have revealed that SUMO system is involved in cancer metastasis. In this review, we will summarize the possible role of SUMO system in cancer development, progression, and metastasis and discuss future directions.

Small ubiquitin-like modifiers in cellular malignancy and metastasis.

Prostaglandin E2 (PGE2) is known to have a key role in the development of colorectal cancer, but previous experiments showed its contrasting (i.e. tumor-promoting or tumor-suppressive) roles depending on experimental conditions. To elucidate the mechanisms underlying such contrasting roles of PGE2 in tumorigenesis, we investigated all the previous experiments and found a new signal transduction pathway mediated by retinoic acid receptor-related orphan receptor (ROR)α, in which PGE2/PKCα-dependent phosphorylation of RORα attenuates Wnt target gene expression in colon cancer cells. From mathematical simulations combined with biochemical experimentation, we revealed that RORα induces a biphasic response of Wnt target genes to PGE2 stimulation through a regulatory switch formed by an incoherent feedforward loop, which provides a mechanistic explanation on the contrasting roles of PGE2 observed in previous experiments. More interestingly, we found that RORα constitutes another regulatory switch formed by coupled positive and negative feedback loops, which regulates the hysteretic response of Wnt signaling and eventually converts a proliferative cellular state into an anti-proliferative state in a very delicate way. Our results indicate that RORα is the key regulator at the center of these hidden switches that critically regulate cancer cell proliferation and thereby being a promising anti-cancer therapeutic target.

The hidden switches underlying RORα-mediated circuits that critically regulate uncontrolled cell proliferation

We have recently identified a cDNA for a ubiquitin-specific protease (UBP), UBP41, that encodes the smallest functional UBP identified to date, using an Escherichia coli-based in vivo screening method. In the present study we isolated highly related cDNAs encoding a new family of UBP enzymes, named UBP46, UBP52 and UBP66. These UBPs have virtually identical catalytic domains spanning the sequence of UBP41 between the active-site Cys and the His box (95% identity). However, they possess distinct N- and/or C-terminal extensions. Moreover, they are more closely related to each other than to any other members of the UBP family. Thus these chick UBPs must define a novel family of de-ubiquitinating enzymes and should represent the first example among the UBP family enzymes, whose multiplicity is achieved by variation in their N- and C-terminal extensions. The chick UBPs were expressed in E. coli, and purified from the cells to apparent homogeneity using 125I-labelled ubiquitin-alphaNH-MHISPPEPESEEEEEHYC as a substrate. Each of the purified UBP46, UBP52 and UBP66 enzymes behaved as proteins of similar sizes under both denaturing and non-denaturing conditions, suggesting that all of them consist of a single polypeptide chain. The UBP enzymes cleaved the C-terminus of the ubiquitin moiety in natural and engineered fusions irrespective of their sizes and thus are active against ubiquitin-beta-galactosidase as well as a ubiquitin C-terminal extension protein of 80 amino acids. All UBPs except UBP66 released free ubiquitin from poly-His-tagged di-ubiquitin. However, the isopeptidase activity for hydrolysing polyubiquitinated lysozyme conjugates was not detected from these UBPs, which makes these UBPs distinct from UBP41. These results suggest that the chick UBPs may play an important role in production of free ubiquitin from linear polyubiquitin chains and of certain ribosomal proteins from ubiquitin fusion proteins.

Sung Hee Baek

Papers

Nuclear receptor coregulators: their modification codes and regulatory mechanism by translocation.

Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases

Small ubiquitin-like modifiers in cellular malignancy and metastasis.

The hidden switches underlying RORα-mediated circuits that critically regulate uncontrolled cell proliferation

A novel family of ubiquitin-specific proteases in chick skeletal muscle with distinct N- and C-terminal extensions.